This is a first resubmission of a K23-Mentored Patient-Oriented Research Career Development Award application entitled "MRS Studies of Glutamate and GABA in Bipolar Disorder". The candidate's background is in postmortem studies of cellular abnormalities in bipolar disorder (BD), and he is currently the Director of the Schizophrenia and Bipolar Disorder Program at McLean Hospital. The current proposal is designed to allow the candidate to use in vivo neuroimaging to extend his findings of cellular abnormalities in BD. Magnetic resonance spectroscopy (MRS) is an excellent technique for this purpose, and the candidate has chosen to work under the mentorship of Dr. Perry Renshaw, a leading MRSexpert and director of McLean's Brain Imaging Center. Given his direct involvement in the clinical care of patients with BD and relationship with a leading MRS research group, the candidate is well-positioned to develop an independent research program applying MRS approaches to BD studies. It is hoped that this will lead to a better understanding of BD pathophysiology and current treatments, as well as to identification of novel treatment targets. The main goal of the proposed research is to use recently developed MRS approaches to quantify brain glutamate and gamma-aminobutyric-acid (GABA) levels in BD patients and healthy controls. Glutamate and GABA are the most abundant neurotransmitters in the brain, and extensive neuronal-glial interactions are required for their function. Their levels therefore provide information on synaptic function and cellular activity. The central hypothesis of the application is that cellular abnormalities in BD will be systemactically reflected in glutamate and GABA abnormalities. Glutamate and GABA levels will be measured in the anterior cingulate cortex where abnormalities have been reported in BD, and in the parieto-occipital cortex. The candidate will take advantage of his ability to recruit patients from a clinical unit specializing in BD to examine the effects of phase of illness (recurrent vs. first-episode) and disease episode (patients in manic and depressive episodes in both cohorts, as well as medicated and medication-free euthymic outpatients) on the measures. Statistical analyses will be tailored to examine the effects of these factors on glutamate and GABA levels. As part of proposed research, the candidate seeks training in: 1) MRS techniques and methods for MRS data analysis;2) neurochemistry of synaptic transmission and cellular metabolism;and 3) ethical clinical research methods. The proposed research plan, didactic courses, and work with mentors and advisors will foster the candidate's development into an independent clinician-scientist using neuroimaging to study BD neurochemistry. BD is a common and debilitating illness. Current BD treatments are partially effective, and their mechanisms of action are not well-understood. There is therefore a pressing need for effective novel treatments which target relevant biological processes in BD, and the current proposal aims to contribute to meeting this need.